The long-term objective of our investigations is to examine when, where, and how the pharmacokinetics of organic nitrates may relate to their pharmacologic and therapeutic effects. Our preliminary findings suggest that there are some unique features in the uptake of nitroglycerin by blood vessels. Since vasodilation is the predominant pharmacologic action of nitrates, it appears useful to investigate the kinetics of nitrates in this probable target tissue (i.e., blood vessels) and examine how nitrate concentrations in it may relate to vasodilation. The relationship between plasma and blood vessel nitrate concentration will also be studied. In human studies, we showed that plasma isosorbide dinitrate (ISDN) concentrations were paradoxically elevated during chronic dosing while nitrate tolerance was concomitantly developed. In animal studies, we showed that ISDN metabolites can also decrease ISDN plasma clearance. It is not known, however, whether this metabolite interaction also affects tissue binding of ISDN, particularly at the blood vessel sites. A possible contributing mechanism of ISDN tolerance may be hypothesized as follows: Chronic ISDN administration leads to increased concentrations of nitrated metabolites, one or both of which may inhibit tissue (blood vessel) uptake of ISDN. Thus, during chronic therapy, the diminished tissue uptake leads to a reduced vasodilator response even though the same dose of ISDN is maintained. Studies are proposed in this application to test this hypothesis.